CN114903892A - Application of marine Piericidin F and derivatives thereof in treatment of cervical cancer - Google Patents
Application of marine Piericidin F and derivatives thereof in treatment of cervical cancer Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses application of a marine microorganism-derived compound 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol (Piericidin F) in treatment of E6/E7 positive cervical cancer, and experiments prove that the Piericidin F can effectively inhibit HeLa proliferation of a human cervical cancer cell in vitro and inhibit formation of HeLa cell monoclone. Experiments have found that Piericidin F can induce the degradation of oncoprotein E6/E7 by UPS and inhibit its function. Piericidin F can be obtained from marine microorganisms, is easy to separate and extract, and is an antitumor drug with a good application prospect.
Description
One, the technical field
The invention relates to application of a novel marine microorganism-derived compound 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol 6-methoxy-2- ((2E,5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethylpyridine-2, 5,7, 11-tetramethylpyridine-4-ol Piericin F) in treatment of E6/E7 positive cervical cancer, and belongs to the field of chemicals.
Second, background Art
Cervical cancer is the most common gynecological malignancy, second to breast cancer. At present, more than 46 ten thousand new cases of cervical cancer are worldwide discovered every year, while more than 13 ten thousand new cases of cervical cancer account for more than 28 percent of global cases every year in China, and clinical cases show that the cervical cancer is characterized by regional growth and advanced onset age in recent years. The cervical cancer clinical practice guideline published by the united states National Comprehensive Cancer Network (NCCN) in 2018 shows that cisplatin-based chemotherapy is a main clinical treatment method for cervical cancer. However, chronic use of cisplatin and its derivatives can lead to severe drug resistance with associated nephrotoxicity, ototoxicity and myelosuppression. There are many causes for inducing cervical cancer, and among them, persistent infection with high-risk Human Papillomavirus (HPV) is the most important cause for inducing cell canceration. Studies have shown that more than 90% of cervical cancers are associated with HPV infection. After infecting HPV virus, the virus gene is integrated into host cell genome to express pathogenic cancer protein E6/E7, which is the main pathogenic factor of cervical cancer. Because these two oncogenic proteins are selectively expressed in tumor cells, E6/E7 has been extensively studied as a potential target for E6/E7-positive cervical cancer therapy.
At present, a plurality of researches show that the natural product can target HPV E6/E7 oncoprotein at different levels and has good anti-cervical cancer activity. For example, tanshinone IIA and wogonin derived from Chinese herbal medicines can induce apoptosis of cervical cancer cells by down-regulating E6/E7 at the transcriptional level. Therefore, the search of a candidate targeting the oncoprotein E6/E7 in natural products as a potential cervical cancer resistant lead compound is a promising strategy.
Piericidins are a class of alpha-pyridone compounds produced by Streptomyces, and since the discovery in 1965, 5 classes including over 20 Piericidin classes of compounds have been isolated. Recent studies indicate that the Piericidin compounds have good antitumor activity in addition to antibacterial, anti-insect and vasodilatation activities. Therefore, we isolated and characterized a novel Piericidin alkaloid, Piericidin F, from a non-productive mutant of Streptomyces CHQ-64, investigated the cytotoxicity of Piericidin F on human cervical cancer HeLa cells, and attempted to elucidate the molecular mechanism of its activity.
The invention has not previously applied Piericidin F to the treatment of E6/E7 positive cervical cancer. And Piericidin F can be separated and extracted from streptomyces, is easy to obtain, can inhibit the proliferation of Hela cells, and is a promising antitumor drug.
The chemical name of 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol is 36-methoxy-2- ((2E,5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethylthideca-2, 5,7, 11-tetra-1-yl) -3-methylpyridin-4-ol (Piericidin F) has a chemical structure shown in figure 1.
Third, the invention
One of the objects of the present invention is to demonstrate the effect of Piericidin F against E6/E7 positive cervical cancer.
The second purpose of the invention is to detect the influence of Piericidin F on HeLa cell inhibition and clone formation in vitro.
The invention also aims to detect the influence of Piericidin F on HeLa cell apoptosis and mitochondrial membrane potential.
The fourth purpose of the invention is to explore the influence of Piericidin F on the expression and function of E6/E7 protein.
The fifth purpose of the invention is to explore the degradation pathway of Piericidin F for inducing E6/E7 protein degradation.
In order to realize the purpose, the invention adopts the technical scheme that:
the MTT technology is adopted to detect the inhibition effect of Piericidin F on the proliferation of human cervical cancer cells (HeLa) positive to E6/E7.
The plate cloning technology is adopted to detect the influence of Piericidin F on the formation of HeLa cell monoclone in vitro.
The influence of Piericidin F on HeLa cell apoptosis is detected by using Hoechst 33342 staining, WesternBlotting and MTT technology.
The influence of Piericidin F on the Mitochondrial Membrane Potential (MMP) of HeLa cells is detected by adopting a flow cytometry and SRB method.
And detecting the influence of Piericidin F on the oncoprotein E6/E7 and the function thereof by using a Western Blotting technology.
A Western Blotting technology is adopted to explore the degradation pathway of the oncoprotein E6/E7.
Compared with the prior art, the invention has the advantages and the technical effects that: the invention proves the effect of Piericidin F on resisting E6/E7 positive cervical cancer, and finds that the Piericidin F has obvious inhibition effect on HeLa cells, compared with the traditional chemotherapeutic drugs and targeted drugs, the compound can play a role from a pathogenic source E6/E7, but not a non-specific cytotoxic effect or a downstream signal path of E6/E7. Meanwhile, the molecular mechanism of treating E6/E7 positive cervical carcinoma is systematically elucidated.
Piericidin F is effective in inhibiting proliferation of human cervical cancer cells (HeLa) in vitro. Meanwhile, Piericidin F can also inhibit the formation of HeLa cell monoclonals in vitro, and can induce the HeLa cells to undergo caspase-dependent apoptosis and destroy the mitochondrial function of the HeLa cells. We further explored the molecular mechanism of Piericidin F for inhibiting HeLa cell proliferation, and found that Piericidin F can degrade oncoprotein E6/E7 and inhibit its function. Furthermore, Piericidin F induced degradation of oncoprotein E6/E7 by UPS. The results show that Piericidin F has good anti-tumor effect on E6/E7 positive cervical cancer cells and has wide application prospect.
Description of the drawings
FIG. 1 shows the chemical structure of Piericidin F in the present invention.
FIG. 2 shows that Piericidin F can inhibit proliferation of HeLa of E6/E7 positive cervical cancer cell in vitro.
FIG. 3 shows that Piericidin F in the present invention can induce caspase-dependent apoptosis in HeLa cells.
FIG. 4 shows that Piericidin F is able to disrupt mitochondrial function in HeLa cells in accordance with the present invention.
FIG. 5 shows that Piericidin F of the invention is able to degrade oncoprotein E6/E7 and inhibit its function.
FIG. 6 shows that Piericidin F in the present invention is able to induce the degradation of E6/E7 by UPS.
Fifth, detailed description of the invention
The technical scheme of the invention is further explained in detail by combining the attached drawings and test examples.
Test example 1
The influence of Piericidin F on the inhibition of the proliferation of human papilloma virus positive cervical cancer cell HeLa in vitro is explored.
Cell: human cervical cancer cells (HeLa), purchased from shanghai cell bank, china academy of sciences.
Reagent: piericidin F; giemsa dye liquor; MTT; doxorubicin; DMSO.
The instrument comprises the following steps: CO 2 2 An incubator; inverting the microscope; an enzyme-labeling instrument; an ultra-clean workbench.
Experimental method MTT method: HeLa cells in a logarithmic growth phase are inoculated into a 96-well plate, Piericidin F with different concentrations is added into an experimental group after the cells are attached to the wall, DMSO diluted in equal proportion is added into a control group, adriamycin is set as a positive control (the concentration is 1 mu M), and meanwhile, a culture medium control is added. Standing at 37 deg.C for CO 2 Culturing in 5% incubator for 72 h. After the incubation, 20. mu.L of MTT solution was added to each well and the incubation was continued in the incubator for 4 h. After the incubation, the supernatant was discarded, 150. mu.L of DMSO was added to each well, and the wells were incubated in an oven at 37 ℃ for 10min, and then the absorbance (OD) was measured at a wavelength of 570nm using a microplate reader. At the same time, the cell death rate and IC were calculated using SPSS statistical software 50 。
Experimental methods plate cloning method: taking HeLa cells in logarithmic growth phase, planting 800 cells in each well into a 6-well plate, and placing the cells in an incubator for 24 h. After the cells were adherent, the cells were treated with varying concentrations of Piericidin F and incubated for 8 days. After the drug effect is finished, the upper layer culture medium is discarded, and PBS is added to clean the cells. Then adding methanol for fixation for 3min, discarding the methanol, and adding Giemsa dye solution for dyeing for 15 min. Finally, the staining results were photographed and the clones were counted.
From the experimental results of FIG. 2, it was found that P was present after 24, 48 and 72 hours of treatmentIC of iericidin F on HeLa cells 50 386.71, 75.18 and 28.80nM, respectively, indicating that Piericidin F inhibits HeLa cell proliferation in a concentration and time dependent manner. In addition, the cytotoxicity of Piericidin F on HeLa cells was also confirmed by clonogenic assays. The results show that clone formation of HeLa cells was significantly reduced after Piericidin F treatment and the clone number decreased in a concentration-dependent manner. The results show that the Piericidin F can inhibit the in-vitro proliferation of HeLa cells of human cervical cancer.
Test example 2
The influence of Piericidin F on HeLa cell apoptosis was explored.
Cell: human cervical cancer cells (HeLa), purchased from shanghai cell bank, china academy of sciences.
Reagent: piericidin F; hoechst 33342; Z-VAD-fmk; protein electrophoresis liquid; film transferring liquid; MTT; 1 × Loading Buffer; 4 × upper layer concentrated gel buffer; 4 Xthe lower layer separation gel buffer solution; an APS; NC film; pre-staining a Marker with protein; ECL luminescence kits; DMSO.
The instrument comprises: CO 2 2 An incubator; inverting the microscope; an ultra-clean bench; a flow cytometer; a high speed refrigerated centrifuge; a protein electrophoresis apparatus; shaking table; ST-II type transfer electrophoresis tank; FluorChem E multifunctional imaging analysis system.
Experimental method Hoechst 33342 staining experiment: taking HeLa cells in logarithmic phase, inoculating 20 ten thousand per hole into a 6-hole plate, and placing the culture plate in a cell culture box to wait for the cells to adhere to the wall. Adding DMSO diluted by equal times into a solvent control group, adding Piericidin F with different concentrations into an experimental group, and placing the experimental group in an incubator for further culture for 36 h. After the drug effect is over, the upper layer culture medium is discarded, precooled PBS is added to wash the cells, 500 mu L of Hoechst 33342 dye with the final concentration of 5 mu g/mL is added to each hole, and incubation is carried out for 30min at 37 ℃. After the staining was finished, the staining was observed by using a fluorescent inverted microscope and photographed at 400X.
Experimental methods Western Blotting method: HeLa cells in logarithmic growth phase were seeded in six-well plates (2X 10 per well) 5 Individual cells) and treated with different concentrations of Piericidin F for 24 h. The cells were then harvested and centrifuged at 1000rpm for 5min at 4 ℃. Washing with PBSThereafter, the cells were lysed with 1 × Loading Buffer at 4 ℃ for 45 min. After completion of lysis, boiling for 15min and storing at-20 ℃. Protein samples were separated electrophoretically on 6-12% SDS-PAGE gels and transferred to NC membranes. After cutting the target strip, the NC membrane was sealed with 5% skim milk for 1h and incubated with the primary antibody of the target strip overnight at 4 ℃. The NC membrane was then incubated with secondary antibody at room temperature for 1h and detected by chemiluminescence on a developer.
According to the experimental result shown in FIG. 3, the HeLa cells after 36h of Piericidin F action show brighter blue fluorescence compared with the control group, which indicates that Piericidin F can induce HeLa cells to undergo apoptosis. Furthermore, C-PARP, C-Cas3 and C-Cas9 increased, while Cas3 and Cas9 decreased after treatment with Piericidin F compared to the control group. Furthermore Bax is up-regulated, while Bcl-2 is down-regulated. In addition, the DNA damage marker γ -H2AX was increased, while the apoptosis-inhibiting protein Survivin was decreased. Moreover, the changes of the apoptosis-related proteins are concentration-dependent. These results further indicate the occurrence of apoptosis. To investigate whether Piericidin F-induced apoptosis was dependent on caspase activation, HeLa cells were pre-treated with the pan-caspase inhibitor Z-VAD-fmk and then incubated with varying concentrations of Piericidin F. The results show that HeLa cells pre-incubated with the pan-caspase inhibitor are less sensitive to Piericidin F than HeLa cells incubated with Piericidin F alone, indicating that Piericidin F-induced apoptosis is dependent on caspase activation. The results show that Piericidin F induces caspase-dependent apoptosis in HeLa.
Test example 3
The effect of Piericidin F on mitochondrial function of HeLa cells was explored.
Cell: human cervical cancer cells (HeLa), purchased from shanghai cell bank, china academy of sciences.
Reagent: piericidin F; DMSO; PBS; rhodamine 123; SRB dyes.
The instrument comprises: CO 2 2 An incubator; inverting the microscope; an ultra-clean bench; a flow cytometer; a high speed refrigerated centrifuge; a microplate reader.
Experimental methods flow cytometry: taking HeLa cells in logarithmic phase, inoculating 20 ten thousand per hole into a 6-hole plate, and placing the culture plate in a cell culture box to wait for the cells to adhere to the wall. Adding DMSO diluted by equal times into solvent control wells, respectively adding Piericidin F with different concentrations into experimental groups, and culturing for 36 h. After the drug action is finished, removing the upper layer culture medium, adding pancreatin digestive cells, collecting cell samples in a flow tube, centrifuging at 4 ℃, 1200rpm for 5min, removing supernatant, adding precooled PBS for resuspension, and repeatedly centrifuging according to the method. 900 μ L of PBS was added to resuspend the cells, and 100 μ L of rhodamine 123 stain (final concentration 3 μ g/mL) was added in the dark and the mixture was stained at 37 ℃ for 20 min. After dyeing is finished, centrifuging at 4 ℃ and 1200rpm for 5min, then removing supernatant, adding precooled PBS for resuspension, repeating the centrifugation step twice, adding 500 mu L PBS for resuspension, and detecting on a machine. The results of the experiment were analyzed with Summit software.
Experimental methods SRB method: taking HeLa cells in logarithmic phase, inoculating 4000/hole to a 96-hole plate, and placing the 96-hole plate in a cell culture box at 37 ℃ for culturing for 24h until the cells adhere to the wall. The next day, after the cells adhered, the upper medium was discarded, and the cells were washed with PBS. After 90 mul of sugar-free or sugar-containing culture medium is added into each hole, Piericidin F with different concentrations is added into each hole of an experimental group, DMSO diluted by equal times is added into a solvent control group, pure water with the same volume is added into a negative control group, and adriamycin is added into a positive control group. Each group is provided with 5 multiple holes and is placed in an incubator for 72 hours. After the drug effect is finished, the upper layer culture medium is discarded, 100 mu L of 10% TCA fixed cells are added into each hole, and the fixed cells are placed in a refrigerator at 4 ℃ for fixing for more than 1 h. The TCA in the 96-well plate was discarded, and the 96-well plate was rinsed 5-6 times with tap water and dried in an oven at 37 ℃. Adding 100 μ L SRB dye into each well, placing 96-well plate in 37 deg.C incubator, dyeing for 15min, washing 96-well plate with 1% glacial acetic acid for 5-6 times, and oven drying at 37 deg.C. After the 96-well plate is dried, 150. mu.L of 10mM Tris-HCl solution is added into each well, and the mixture is placed in an oven at 37 ℃ for incubation until crystals are dissolved. The absorbance (OD) at 515nm was measured with a microplate reader. According to the formula: inhibition ratio [% ] (solvent control group OD-experimental group OD)/solvent control group OD × 100% ] the inhibition ratio of the compound Piericidin F was calculated. And using IC according to the inhibition ratio of different concentrations 50 The calculator calculates the condition that Piericidin F is not sugar or contains sugarIC 72h after exposure to HeLa cells 50 The value is obtained.
From the experimental results shown in FIG. 4, we found that we used Rho-123 probe after treatment. Compared to the control group (10.54%), MMP after Piericidin F acted on HeLa cells decreased significantly, and the percentage of cells with depolarizing MMPs increased to 54.54% and 83.31% after 0.2 and 0.4 μ M PdF action, respectively, indicating that Piericidin F was able to concentration-dependently destroy MMP of HeLa cells. To further confirm whether Piericidin F affects mitochondrial function, we compared Piericidin F cytotoxicity against HeLa cells under normal (G + S +) conditions and glucose deprivation (G-S +) conditions, since tumor cells are more sensitive to chemical agents under conditions of disrupted mitochondrial function. The results showed that HeLa cells cultured under glucose-deficient conditions had higher sensitivity to the action of Piericidin F compared to HeLa cells cultured under normal conditions, confirming that Piericidin F was able to disrupt the mitochondrial function of HeLa cells.
Test example 4
The effect of Piericidin F on oncoproteins E6/E7 and their function was explored.
Cell: human cervical cancer cells (HeLa), human cervical cancer cells (CaSki), human myeloblastosis cells (HL-60), human cervical squamous carcinoma cells (SiHa), and human chronic myeloblastic leukemia cells (K562) purchased from Shanghai cell Bank of China academy of sciences.
Reagent: piericidin F; protein electrophoresis liquid; film transferring liquid; MTT; 1 × Loading Buffer; 4 × upper concentrated gel buffer; 4 Xthe lower layer separation gel buffer solution; APS; NC film; pre-staining a Marker with protein; ECL luminescence kits; DMSO; and (4) SRB dye liquor.
Instrument CO 2 An incubator; inverting the microscope; an ultra-clean bench; a flow cytometer; a high speed refrigerated centrifuge; a protein electrophoresis apparatus; shaking table; ST-II type transfer electrophoresis tank; a fluorochem E multifunctional imaging analysis system; a microplate reader.
Experimental methods Western Blotting method: HeLa cells in logarithmic growth phase were seeded in six-well plates (2X 10 per well) 5 Individual cells) and treated with varying concentrations of Piericidin F for 24 h. The cells were then harvested and incubated at 4 ℃ at 10 deg.CCentrifuge at 00rpm for 5 min. After washing with PBS, cells were lysed with 1 × Loading Buffer for 45min at 4 ℃. After lysis was complete, boiled for 15min and stored at-20 ℃. Protein samples were separated electrophoretically on 6-12% SDS-PAGE gels and transferred to nitrocellulose membranes (NC membranes). After cutting the target strip, the NC membrane was sealed with 5% skim milk for 1h and incubated with the primary antibody of the target strip overnight at 4 ℃. The NC membrane was then incubated with secondary antibody at room temperature for 1h and detected by chemiluminescence on a developer.
Experimental methods SRB method: and (3) taking HeLa cells in the logarithmic growth phase, planting 4000/hole into a 96-well plate, wherein each hole is 80 mu L, and placing the 96-well plate into a cell culture box for culturing for 24h until the cells adhere to the wall. The next day, the medicine is added for action. The experimental groups were treated with cisplatin (0.625-20 μ M) in the presence of 0.05 μ M Piericidin F in HeLa cells, with separate Piericidin F and cisplatin control wells and solvent control wells, doxorubicin as the positive control, and media control wells, 5 duplicate wells per group, placed in a 37 ℃ incubator for 72 h. After the drug effect was completed, the upper medium was discarded, 100. mu.L of 10% TCA was added to each well, and then the 96-well plate was fixed in a 4 ℃ freezer for 1 hour or more. Discard TCA in the plate, wash 96-well plate with tap water for 5-6 times, and dry in 37 deg.C oven. Add 100. mu.L of SRB dye to each well, stain at 37 ℃ for 15min, wash the 96-well plate 5-6 times with 1% glacial acetic acid solution, and oven dry at 37 ℃. After the 96-well plate was dried, 150. mu.L of 10mM Tris-HCl solution was added to each well, and incubated at 37 ℃ until the crystals were dissolved. The absorbance (OD) at 515nm was measured with a microplate reader. According to the formula: inhibition ratio [% ] (solvent control group OD-experimental group OD)/solvent control group OD × 100% ] the inhibition ratio of the compound Piericidin F was calculated. Calcusyn was used to calculate Combination Index (CI) with CI values >1, 1 and <1 indicating antagonism, additive effect and synergy respectively.
According to the experimental results of FIG. 5, Piericidin F was found to significantly reduce the level of E6/E7 in cells in a concentration-dependent manner and a time-dependent manner. Furthermore, the down-regulation of E6/E7 by Piericidin F was accompanied by an increase in C-PARP, indicating that a decrease in E6/E7 is responsible for Piericidin F-induced HeLa apoptosis. p53 and Rb are the main targets of E6/E7 and are rapidly degraded by E6/E7. Due to the fact thatWe hypothesized that Piericidin F-induced down-regulation of E6/E7 might lead to up-regulation of p53 and Rb. P53 and Rb proteins increased in a concentration-dependent manner following Piericidin F treatment. Furthermore, we also tested E6/E7 changes in other HPV-positive cervical cancer cell lines after Piericidin F action, such as CaSki and SiHa. As shown, Piericidin F significantly reduced the levels of E6/E7 in CaSki and SiHa cells, while the levels of C-PARP increased significantly with the decrease in E6/E7, and Piericidin F also showed a significant effect on CaSki (IC) 50 3.70 μ M) and SiHa (IC) 50 5.35 μ M) was observed.
E6/E7 has been reported to activate the PI3K/AKT signaling pathway and the STAT 3-mediated signaling pathway, which are required for cervical cells to become cancerous. After oncoprotein E6/E7 was reduced by Piericidin F, the phosphorylation levels of AKT and STAT3 were significantly reduced, while the background protein levels of AKT and STAT3 were unaffected. These results indicate that oncoprotein E6/E7 is degraded by Piericidin F and loses the function of signaling downstream. To determine whether the reduction in STAT3 and AKT phosphorylation in HeLa cells was caused by a reduction in E6/E7, we examined the levels of p-STAT3 and p-AKT in E6/E7 negative HL-60 and K562 cell lines. As shown, the background proteins of STAT3 and AKT and their levels of phosphorylation did not change significantly after treatment with Piericidin F, indicating that Piericidin F did not directly affect the levels of phosphorylation of STAT3 and AKT, but rather affected the activation of STAT3 and AKT by downregulating E6/E7 levels. Activation of AKT and STAT3 was reported to contribute to resistance of HeLa cells to cisplatin. Therefore, inhibition of AKT and STAT3 activation may make HeLa cells more sensitive to cisplatin. Therefore, we examined the combined effect of Piericidin F and cisplatin on HeLa cells. The results show that the CI index is much less than 1, indicating that the combined administration of Piericidin F and cisplatin shows a significant synergistic effect in inhibiting HeLa cell proliferation. These results demonstrate that Piericidin F can reduce oncoprotein E6/E7 levels and subsequently inhibit their signaling function.
Test example 5
The pathway of Piericidin F to degrade oncoproteins E6/E7 was explored.
Cell: human cervical cancer cells (HeLa), purchased from shanghai cell bank, china academy of sciences.
Reagent: piericidin F; protein electrophoresis liquid; film transferring liquid; MTT; 1 × Loading Buffer; 4 × upper layer concentrated gel buffer; 4 Xthe lower layer separation gel buffer solution; NC film; pre-staining a Marker with protein; ECL luminescence kit
The instrument comprises: CO 2 2 An incubator; inverting the microscope; an ultra-clean bench; a flow cytometer; a high speed refrigerated centrifuge; a protein electrophoresis apparatus; shaking table; ST-II type transfer electrophoresis tank; FluorChem E multifunctional imaging analysis system.
Experimental methods Western Blotting method: HeLa cells in logarithmic growth phase were seeded in six-well plates (2X 10 per well) 5 Individual cells) and treated with different concentrations of Piericidin F for 24 h. The cells were then harvested and centrifuged at 1000rpm for 5min at 4 ℃. After washing with PBS, the cells were lysed with 1 × Loading Buffer for 45min at 4 ℃. After lysis was complete, boiled for 15min and stored at-20 ℃. Protein samples were separated electrophoretically on 6-12% SDS-PAGE gels and transferred to NC membranes. After cutting the target strip, the NC membrane was sealed with 5% skim milk for 1h and incubated with the primary antibody of the target strip overnight at 4 ℃. The NC membrane was then incubated with secondary antibodies for 1h at room temperature and detected by chemiluminescence by a developer.
According to the experimental results of FIG. 6, it was found that in the presence of CHX (a translation inhibitor), E6/E7 decreased more rapidly after Piericidin F action, compared to the control group, indicating that Piericidin F accelerated the degradation of E6/E7 at the protein level. In cervical cancer cells, levels of E6/E7 are regulated by UPS. To determine whether proteasomes were involved in Piericidin F-induced degradation of E6/E7, we used the proteasome inhibitor MG132 to detect levels of E6/E7 after Piericidin F treatment. The results show that Piericidin F alone induced down-regulation of E6/E7, while MG132 reversed this reduction, indicating that proteasomes mediated Piericidin F-induced degradation of E6/E7. Furthermore, in the presence of Piericidin F, the levels of C-PARP were reduced by MG132, further demonstrating that degradation of E6/E7 triggers Piericidin F-induced apoptosis. These results indicate that UPS is activated by Piericidin F to increase the degradation of oncoprotein E6/E7 and also mediates apoptosis of HeLa cells.
Proteins are usually ubiquitinated before being degraded by the proteasome. We examined the ubiquitination level of E6 protein after Piericidin F action by IP experiments. The results show that Piericidin F increased the ubiquitination level of E6 protein and appeared time-dependent compared to the blank group, further indicating that UPS is involved in Piericidin F-induced E6/E7 degradation.
Claims (7)
- The use of 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol and its derivatives for the treatment of E6/E7 positive cervical cancer, having the chemical formula:
- 2. the anti-cervical cancer effect of claim 1, wherein said tumor cells are: a human cervical cancer cell line positive for E6/E7.
- 3. The use according to claim 1 for the treatment of cervical cancer, wherein: the 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol can be used for preparing a medicine for treating E6/E7 positive cervical cancer.
- 4. The use according to claim 1 for the treatment of cervical cancer, wherein: the 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol can effectively inhibit the proliferation of HeLa cells in vitro.
- 5. The use according to claim 1 for the treatment of cervical cancer, wherein: the 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol can induce caspase-dependent apoptosis in HeLa cells.
- 6. The use according to claim 1 for the treatment of cervical cancer, wherein: the 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol can destroy the mitochondrial membrane potential of HeLa cells.
- 7. The use according to claim 1 for the treatment of cervical cancer, wherein: the 6-methoxy-2- (((2E, 5E,7E,11E) -10-methoxy-3,7,9, 11-tetramethyltridecyl-2, 5,7,11-tetraen-1-yl) -3-methylpyridin-4-ol can induce the degradation of E6/E7 protein through UPS pathway and inhibit the function of the protein.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008174508A (en) * | 2007-01-19 | 2008-07-31 | National Institute Of Advanced Industrial & Technology | New piericidine derivative or its salt, method for producing the same and antitumor agent containing the derivative as active ingredient |
| CN109414419A (en) * | 2016-06-15 | 2019-03-01 | 德国癌症研究中心 | Treatment of cancer is carried out by targeted energy metabolism simultaneously and internal pH |
| WO2020234454A1 (en) * | 2019-05-23 | 2020-11-26 | Deutsches Krebsforschungszentrum | Combination treatment of cancer targeting energy metabolism and intracellular ph |
| US20220079912A1 (en) * | 2018-09-14 | 2022-03-17 | University Of Mississippi | Anticancer formulation |
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- 2021-02-09 CN CN202110175637.4A patent/CN114903892A/en active Pending
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| JP2008174508A (en) * | 2007-01-19 | 2008-07-31 | National Institute Of Advanced Industrial & Technology | New piericidine derivative or its salt, method for producing the same and antitumor agent containing the derivative as active ingredient |
| CN109414419A (en) * | 2016-06-15 | 2019-03-01 | 德国癌症研究中心 | Treatment of cancer is carried out by targeted energy metabolism simultaneously and internal pH |
| US20220079912A1 (en) * | 2018-09-14 | 2022-03-17 | University Of Mississippi | Anticancer formulation |
| WO2020234454A1 (en) * | 2019-05-23 | 2020-11-26 | Deutsches Krebsforschungszentrum | Combination treatment of cancer targeting energy metabolism and intracellular ph |
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